Investigating voltage activated potassium and proton channels

2019-04-25Simulating the nature of voltage activated systems is a problem of major current interest, covering the action of voltage gated ion channels to energy storage batteries. However, fully microscopic converging molecular simulations of external voltage effects present a major challenge and macroscopic models are associated with major uncertainties about the dielectric treatment and the underlying physical basis. Recently, we developed a coarse-grained (CG) model that represents explicit the electrodes, the electrolytes and the membrane / protein system. The CG model provides a semi-macroscopic way for capturing the microscopic physics of voltage activated systems. Our method was originally validated by reproducing macroscopic and analytical results for key test cases and then used in modeling voltage activated ion channels and related problems. In this work, we further establish the reliability of the CG voltage model by comparing it to the results of Monte Carlo (MC) simulations with a microscopic electrolyte model. The comparison explores different aspects of membrane, electrolytes, electrodes systems ranging from the Gouy-Chapman model to the determination of the electrolyte charge distribution in the solution between two electrodes (without and with separating membrane), as well as the evaluation of gating charges. In addition to this work, we explored our voltage-activated ion channel study to proton transport proteins, Hv1, found in diverse cells in humans and other organisms. Our study focuses on evaluating the free energy of transporting a proton through the channel, as well as the effect of the proton transfer through D112, in both the closed and open channel conformations. It is found that D112 allows a transported proton to bypass the electrostatic barrier of the open channel, while not being able to help in passing the barrier in the closed form. This reflects the change in position of the gating-related arginine residues relative to D112, upon voltage-activation. Significantly, the effect of D112 accounts for the observed trend in selectivity by overcoming the electrostatic barrier at its highest point. Thus, the calculations provide a structure/function correlation for the Hv1 system. The present work also clarifies that the action of Hv1 is not controlled by a Grotthuss mechanism but, as is always the case, by the protein electrostatic potential at the rate limiting barriers